Not Applicable
1. Field of the Invention
This invention relates generally to drug compositions that optimize or maximize the therapeutic effects of particular receptor-specific agonists, while concurrently preventing or, in the least, significantly ameliorating receptor desensitization, and which derive from the methodology of the inventor""s U.S. Pat. No. 5,597,699. More particularly, the instant invention sets forth the methodological improvements, and compositions, that are derived from application of that patent""s teachings. These improvements usher in classes of compositions that are pharmaceutically compensated (or fitted) to harmonize with physiologies of diverse therapy recipients.
2. Discussion of Relevant Art
An agonist is a substance/drug that has affinity for and stimulates physiologic activity at cell receptors that are normally stimulated by naturally occurring substances. As used throughout, an agonist is such a substance/drug that produces a maximal or a nearly maximal response, whereas an antagonist or inhibitor is a substance or molecule that produces no response, but can block the action of the drug-agonist. A partial agonist produces a moderate response and can also block the response of the receptor to the agonist-compound. A competitive antagonist is a substance that competes with the agonist for the receptor, but produces no response. [Note: Hereinafter, the combination of a specific agonist with a suitable antagonist or inhibitor will have one of the identifying forms of notation: agonist-antagonist or agonist/antagonist or antagonist: agonist; in such instances, the dash (-), slash (/) and semicolon (:) connoting the same.]
More than twenty years ago, the idea that beta-adrenergic antagonists could be used to treat heart failure was considered heretical although clinical data were emerging to support this viewpoint (White, D. C., Hata, J. A., Shah, A. S., Glower, D. D., Lefkowitz, R. J., and Koch, W. J., xe2x80x9cPreservation of myocardial xcex2-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.xe2x80x9d PNAS, 97: 5428-5433 (2000) and references therein). Previously it was thought that failing hearts required positive inotropic support and that the use of beta-antagonists would depress heart function. After more than two decades, the conventional wisdom on this point has been overturned.
In heart failure, there is a biochemical alteration of the xcex2-adrenergic receptor signaling system leading to the loss of cardiac inotropic reserve through xcex2-adrenergic receptor desensitzation. It was demonstrated in a recent study (White, D. C., et al.) that observed desensitization and down-regulation of xcex2-adrenergic receptors, seen in the failing heart, is deleterious for normal heart function (see 2 and references therein). In this study, paraphrasing what the authors wrote:
(1) In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical xcex2-adrenergic receptor abnormalities seen in human heart failure, delivery of the xcex2-adrenergic receptor kinase ct transgene at the time of myocardial infarction prevents the rise in xcex2-adrenergic receptor kinase 1 activity and expression and thereby maintains xcex2-adrenergic receptor density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of xcex2-adrenergic receptor signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of xcex2-adrenergic receptor kinase 1 and preservation of myocardial xcex2-adrenergic receptor function.
(2) The most promising current therapies in heart failure is the use of xcex2-adrenergic receptor antagonists, which presumably block the chronic activation of the xcex2-adrenergic receptor system by norepinephrine. xcex2-adrenergic receptor kinase 1 up-regulation could be the xe2x80x9cfirst-responsexe2x80x9d feedback mechanism responding to the enhanced sympathetic nervous system activity because the expression of xcex2-adrenergic receptor kinase 1 in the heart can be stimulated by catecholamine exposure. An opposing hypothesis, however, is that the increase in myocardial G protein-coupled receptor kinase (GRK) activity often observed in the failing heart can mediate changes within the xcex2-adrenergic receptor system that are not protective but that rather take part in the pathogenesis of heart failure. If such is the case, then the inhibition of xcex2-adrenergic receptor kinase 1 might represent a novel therapeutic target in the treatment of the failing heart.
(3) To address specifically the issue of whether xcex2-adrenergic receptor desensitization might have maladaptive rather than adaptive consequences in the setting of heart failure, we have delivered a peptide inhibitor of xcex2-adrenergic receptor kinase 1 activity via in vivo intracoronary adenoviral-mediated gene delivery to the hearts of rabbits that have a surgically induced myocardial infarction (MI). We have shown previously that this model of MI in rabbits results in overt heart failure within 3 weeks, including pleural effusions, ascites, and significant hemodynamic dysfunction.
(4) The conventional view of the role of sympathetic activation in heart failure is that the resultant elevated myocardial xcex2-adrenergic receptor kinase 1 levels and xcex2-adrenergic receptor desensitization in the dysfunctional heart are actually protective mechanisms. Abrogation of such compensatory mechanisms, it has been reasoned, would only worsen the physiologic deterioration caused by excess catecholamine stimulation. Indeed, the chronic use of xcex2-agonists in heart failure is harmful.
(5) First, administration of an oral xcex2-agonist leads to further xcex2-adrenergic receptor down-regulation in the lymphocytes of patients with heart failure. Additionally, the xcex2-adrenergic receptor kinase 1 expression is increased after xcex2-adrenergic receptor stimulation. Therefore, the use of xcex2-agonists in heart failure patients exacerbates disturbances in the myocardial xcex2-adrenergic receptor system, leading to further receptor down-regulation and increases in xcex2-adrenergic receptor kinase 1. In contrast, restoration of xcex2-adrenergic receptor signaling through gene delivery of the xcex2-adrenergic receptor kinase ct has a fundamentally opposite effect at a molecular level, i.e., it preserves the number of xcex2-adrenergic receptors and inhibits xcex2-adrenergic receptor kinase 1. [end paraphrasing]
It is interesting that xcex2-adrenergic receptor kinase 1 inhibition shares with xcex2-blockade the potential to normalize or remodel signaling through the cardiac xcex2-adrenergic receptor system in heart failure. Moreover, both treatments lower cardiac GRK activity, enhance catecholamine sensitivity, and raise or preserve myocardial levels of xcex2-adrenergic receptors (White, et al. and included references). Thus, it is possible that part of the salutary effects of xcex2-blockers on the failing heart is because of their demonstrated ability to reduce expression of xcex2-adrenergic receptor kinase 1 in the heart. With the overwhelming positive data showing the beneficial effects of xcex2-blockers in the treatment of heart failure, it is reasonable to question whether the strategy of adding a xcex2-adrenergic receptor kinase 1 inhibitor adds anything novel to the therapeutic armamentarium. However, given the results of this study, it is apparent that xcex2-antagonist therapy and xcex2-adrenergic receptor kinase 1 inhibition may in fact be complementary therapeutic modalities. [See SUMMARY OF THE INVENTION]
Present theories of receptor activation calculate the response of a receptor as some function of an agonist-receptor complex. There have been several modifications and criticisms of receptor theory (see, for example Keen, M.; Testing Models of agonist for G-Protein Coupled Receptors: Trends Pharmacol. Sci. 12, 371-374, 1991), but none of these treatments examined the discrete change induced by ligand binding to two equilibrium states of a receptor and, consequently, no one has developed the instant (and exacting) method for determining actual drug compositions based upon an optimal ratio of agonist to antagonist which effectively prevent desensitization of cellular receptors that are normally and incipiently responsive to a host of agonists. Careful experimental investigations of several different receptor systems have revealed that receptor theory fails to describe the observed responses in a number of cases. Also, the phenomenon of rapid desensitization has been difficult to model by modem receptor theories. Originally many of these experimental observations were reported in 1957 by del Castillo and Katz in their pioneering work on desensitization (del Castillo, J. and Katz, B. Proc. Roy. Soc. Lond. 146, 369-381, 1957). The present theories are inadequate for at least two fundamental reasons; first, they fail to describe relevant experimental observations, except for limited cases and second, they offer only a xe2x80x9cblack boxxe2x80x9d description instead of a physicochemical explanation for receptor response.
In 1991, Geoffrey et al. found that competitive antagonists of a glutamate receptor decreased the desensitization of the receptor (See Geoffrey, M., et al. Molecular Pharmacology 39, 587-591; 1991). They concluded, in this study, that such paradoxical behavior could not be described by the current theories of pharmacologic action deriving from (for example) experimental observations first recorded in 1957 by del Castillo and Katz performing their pioneering work on desensitization. Until most recently, no theory has been able to adequately explain how the behavior observed by Geoffrey et al. occurs; and, the utility of mixing competitive antagonists (or partial agonists) with agonists accurately and, therefore, efficiently to prevent receptor desensitization has been all but overlooked.
Other articles that show the utility (in vivo) of using antagonist/agonist compositions, to prevent receptor desensitization, are extant. One such article is xe2x80x9cAntitacyphylactic Effects of Progesterone and Oxytocin on Term Human Myometrial Contractile Activity In Vitroxe2x80x9d by Xin Fu, MD, Masoumeh Rezapour, MD, Mats Lxc3x6fgren, MD, PhD, Ulf ulmsten, MD, PhD, and Torbjxc3x6rn Bxc3xa4ckstrxc3x6m, MD, PhD, all of the Department of Gynecology and Obstetrics, University Hospital, Uppsala, Sweden and published in Obstetrics and Gynecology (1993; 82: 532-8). Therein, Xin Fu et al. conclude that a quantum of an antagonist, progesterone, is observed to reverse the tachyphylaxis (desensitization) to oxytocin (agonist) of human myometrium. A method for quantifying the compounds for this phenomenon is not suggested, particularly for arriving at proper dosages of the antagonist, for consistently achieving the reversal. Nor for that matter, do Xin Fu et al. provide formulas that will maintain a maximal receptor response.
Another disclosure is of certain importance in the quest for in vivo studies to support modeling investigational techniques in drug research: xe2x80x9cBeta1 and Beta2 Adrenoceptors in the Human Heart: Properties, Function, and Alterations in Chronic Heart Failurexe2x80x9d by Otto-Erich Brxc3x6dde of Bio-chemisches Forschungslabor, Medizinische Klinik and Poliklinik, Abteilung fxc3xcr Nieren-und Hochdruckkrankheiten, Universitxc3xa4tsklinikum, Essen, Germany. (Pharmacological Review, 1991, Vol. 43, No. 2). This is a detailed study on chronic heart failure which discusses a recognized utility of using Beta-AR (beta-adrenergic receptor) antagonists for patients in certain types of heart failure (pp. 228-230) and which hypothesizes that such work by occupying Beta-ARs and prevent desensitization of cardiac Beta-ARs (see p.233 and references therein). [NOTE: No further information is detailed which would inform one of ordinary skill how to quantify the portions of antagonists necessary to fully retard i.e., prevent xe2x80x9cdown-regulationxe2x80x9d (desensitization, ibid p. 233) of Beta-ARs.]
As recently as Jul. 24, 1994, the instant inventor presented his work xe2x80x9cA Novel Biophysical Model for Receptor Activationxe2x80x9d (R. Lanzara, CUNY, New York and Bio-Balance, Inc., New York, N.Y.) to the XIIth International Congress of Pharmacology at Montrxc3xa9al, Quxc3xa9bec, Canada Also presented was a paper published by him concerning Weber""s Law (xe2x80x9cWeber""s Law Modeled by the Mathematical Description of a Beam Balancexe2x80x9d, Mathematical Biosciences, 122:89-94 (1994)). These works are included for their teachings on the instant concept, methods of calculation to provide quanta of antagonist: agonist necessary for achieving the objectives of the invention and demonstrate objectively by use of in vivo empirical studies that the invention is a substantial improvement to the prior art and a significant advancement in the field.
The following of the aforementioned works: Geoffroy et al. xe2x80x9cReduction of Desensitization of a Glutamate Ionotropic Receptor by Antagonistsxe2x80x9d Molecular Pharmacology 39: 587-91 (1991); Xin Fu et al., xe2x80x9cAntitachyphylactic Effects of Progesterone and Oxytocin on Term Human Myometrial Contractile Activity In Vitroxe2x80x9d, Obstetrics and Gynecology, 82: 532-38 (1993); OttoErich Brodde, xe2x80x9cBeta1 and Beta2 Adrenoceptors in the Human Heart: Properties, Function, and Alterations in Chronic Heart Failurexe2x80x9d, Pharmocological Review, Vol. 43, No. 2 (1991); Lanzara, R. xe2x80x9cA Novel Bio-physical Model for Receptor Activationxe2x80x9d Dept. of Allied Health Sci., CUNY, NY, N.Y. and Bio-Balance Inc., NY, N.Y.; and, Lanzara, R. xe2x80x9cWeber""s Law Modeled by the Mathematical Description of a Beam Balancexe2x80x9d, Mathematical Biosciences, 122: 89-94 (1994) are incorporated herein by reference.
The problem is solved for determining the optimal ratio for the concentration of an antagonist- or inhibitor-to-agonist which is sufficient to prevent cellular receptor desensitization, and, without causing unnecessary and unwanted inhibition, maintaining a maximal response. The instant, improved method and formulas describe not only f, the concentration of the antagonist relative to that of the agonist (given by Ki, the dissociation constant of the antagonist, divided by xcfx86, the square root of one-half of the product of the two dissociation constants of the drug-agonist for the receptor), but provide a methodology for obtaining the various formulary factors by which I derive the specific ratios of the selected agonist and antagonist for receptor classes among the diverse animal species. When higher ratios of the antagonist are used, more inhibition of the response occurs; and when lower ratios are used, desensitization results.
It is noted that, in the relevant art, there exists a method for calculating drug efficacy by utilization of easily identifiable biophysical parameters. Additional to both in vitro and in vivo data gleaned from the incorporated references (Xin Fu, et al. and Otto-Erich Brodde, ibid.), I initially had performed an in vitro test on Guinea pig trachea, a widely used substitute tissue for pharmacologic research on human trachea, to determine the optimal composition of an antagonist (propranolol) which is mixed with an agonist (isoproterenol) in order to prevent receptor desensitization produced by a large concentration of said agonist (isoproterenol=25 xcexcM). Specifically, the experimental data and the calculated values were compared. The agreement of the experimental data with the calculated value for f=Ki/xcfx86 was within one and one-quarter percent (1.25%; calculated=0.0395 vs. experimental=0.04). This excellent result validated the method for calculating the optimal ratio of the agonist/antagonist compositions to prevent receptor desensitization. This was a specific test of this invention to determine the optimal ratio of propranolol to isoproterenol in the Guinea pig trachea and proved that there exists a maximally effective ratio that finds utility in its ability to prevent agonist-induced drug desensitization.
The instant method of preventing xcex2-adrenergic receptor desensitization or down-regulation, by creating the optimal ratio of agonist to antagonist combinations, is a complementary therapeutic strategy to what the recent study (White, D. C. et al., ibid.) suggests as an appropriate therapy to maintain xcex2-adrenergic receptor signaling in patients with heart failure. The difference between our approaches is that while the authors of this study advocate the delivery of an intracellular inhibitor of the xcex2-adrenergic receptor kinase through the xe2x80x9cxcex2-adrenergic receptor kinase ct transgenexe2x80x9d, I advocate that, by the proper titration of agonist to antagonist, the same beneficial effects will occur. Many of these effects were mentioned by these authors as resulting from both xcex2-blockade therapy and their own xe2x80x9ctransgene therapyxe2x80x9d. The instant teaching is that, because the endogenous levels of catecholamines are usually elevated in patients with heart failure, concomitant use of xcex2-blockers reduces the desensitization of these receptors in these patients with higher than normal norepinephrine or epinephrine levels. This can be more easily understood by observing that in FIG. 2 of my 1997 patent (Lanzara ""699, ibid.), the use of any inhibitors (xcex2-blockers) will improve the relative response for the desensitized portion of the curve (to the right of the peak). Therefore, the Lanzara compositions represent the best mode of practice to maintain the xcex2-adrenergic signaling in the failing myocardium.
Having been encouraged by initial successes, I have been able to compound a host of pharmaceuticals that are the scientifically derived optimal ratios, i.e., agonist-antagonist, that work best for the largest population, yet have the least side-effect impact. More to the latter characteristic, I have found, through further empirical studies that, relative to heart therapies, the invention""s new compositions presented with significantly less arrhythmias than did agonists alone. A specific composition comprising isoproterenol with metoprolol in the ratio of 1:85, Iso:Met, comprising for a single microgram amount of isoproterenol HCl, 85 micrograms of metoprolol tartrate, is used as a safer and more efficacious alternative to isoproterenol alone. I alter this ratio in a manner normally practiced in the pharmaceutical industry to account for the pharmacokinetic and pharmacodynamic differences between animals and humans and within populations.